tbuckley/cabot-search huggingface dataset:
Patient-reported outcomes for the phase 3 TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer.
Authors: Howard A. Burris III, Takuji Okusaka, Arndt Vogel, Myung Ah Lee, Hidenori Takahashi, Valeriy Vladimirovich Breder, Jean-Frédéric Blanc, Junhe Li, Magdalena Watras, Julia Xiong, Jayne Abraham, Nikunj Patel, Julie Wang, Nana Rokutanda, Gordon Cohen, Do-Youn Oh
Journal: Journal of Clinical Oncology (2022)

4070 Background: TOPAZ-1 (NCT03875235) is a randomized, double-blind, global, Phase 3 study evaluating the efficacy and safety of durvalumab (D) in combination with (+) gemcitabine and cisplatin (GC) as first-line treatment for patients (pts) with advanced biliary tract cancer (BTC). 1 D + GC significantly improved overall survival (OS) versus placebo (PBO) + GC and represents a new treatment option. Methods: A pre-planned secondary objective of TOPAZ-1 was to assess pt-reported outcomes (PROs) for pts receiving D + GC versus PBO + GC. Pts with BTC were randomized 1:1 to D (1500 mg) or PBO, + G (1000 mg/m 2 ) and C (25 mg/m 2 ), for up to 8 cycles, followed by D or PBO monotherapy until disease progression, unacceptable toxicity, or other discontinuation criteria were met. PROs were assessed with the European Organisation for Research and Treatment of Cancer 30-item Quality of Life (QoL) Questionnaire, EORTC QLQ-C30 (C30), and the BTC 21-item module, EORTC QLQ-BIL21 (BIL21). Time to deterioration (TTD) was the primary assessment of PROs; defined as the time from randomization to the date of the first pre-specified, clinically meaningful deterioration (e.g. disease progression). The PRO analysis set included all pts from the full analysis set who completed a questionnaire. Results: Compliance rates for PROs were high at baseline (&gt;81%) and remained high (majority &gt;70% over 28 cycles) for both treatment groups. Baseline scores were comparable between treatment groups. Addition of D was well tolerated, with no significant difference in TTD in D + GC versus PBO + GC for pt-reported symptoms or functioning using either C30 or BIL21 (Table), or Global Health Status/QoL (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.69–1.12; p=0.279). Conclusions: Addition of D to GC improved OS (Oh D-Y, et al. J Clin Oncol 2022;40(suppl 4). Abs 378) and was well tolerated with no difference in TTD of QoL for pts, supporting D + GC as a new treatment option for pts with BTC. Clinical trial information: NCT03875235. [Table: see text]
Clinicopathologic characteristics and treatment outcomes of <i>de novo</i> myeloid sarcoma.
Authors: Justin J. Kuhlman, Benjamin J. McCormick, Talha Badar, James M. Foran, Zaid H. Abdel Rahman, Hemant S. Murthy
Journal: Journal of Clinical Oncology (2022)

e19002 Background: Extramedullary disease in acute myeloid leukemia (AML), also known as myeloid sarcoma (MS), is an uncommon presentation of de novo AML. Clinicopathologic characteristics and optimal treatment strategies of de novo MS remain unclear in both isolated MS without bone marrow (BM) involvement and synchronous MS with BM involvement. Methods: In a single-site retrospective study, medical records of patients with de novo extramedullary AML who received oncological care at any Mayo Clinic site between 1996 and 2021 were analyzed. Using BlueSky Statistics software, survival outcomes were analyzed using Kaplan-Meier and Cox-proportional hazard models for univariate and multivariate analysis, respectively. Results: 83 patients with de novo MS were identified; 49 (59%) presented with synchronous MS and 34 (41%) exhibited isolated MS. Median age at diagnosis was 56 years (range, 17-89); 63% were male. Next-generation sequencing of the blood +/- BM revealed abnormalities in 24/27 (88%) analyzed patients; aberrations included mutations in RTK-RAS pathways (12/27), NPM1 (10/27), TET2 (6/27), and IDH2 (4/27). Median length of follow-up was 1.73 years (95% CI; 0.03-3.0); 53 patients (64%) had expired. Median event free survival was 0.64 years and 0.61 years in isolated and synchronous MS, respectively (p = 0.5). Median overall survival (mOS) in isolated and synchronous MS was 2.1 years and 1.5 years, respectively (p = 0.5). Induction treatment with intensive chemotherapy (IC) was administered in 70 patients (84%). IC regimens included 7+3, MEC, CLAG-M, and hyper-CVAD. Variables associated with improved survival in both groups included treatment with IC +/- allogenic stem cell transplant (alloSCT) (p &lt; 0.001), normal or favorable risk karyotype (p = 0.001), and age less than 60 (p = 0.001). Localized therapy (LT) did not provide an added survival benefit. Patients with synchronous MS were more likely to relapse in the BM and blood than isolated MS (p = 0.02). Conclusions: Enriched with RTK-RAS mutations, de novo MS remains an aggressive form of AML, particularly in patients with intermediate or high-risk genomics or those with skin, soft tissue, or lymphatic involvement. IC should be employed with consideration of alloSCT in eligible patients, particularly in synchronous MS due to a heightened risk for medullary and leukemic relapse.[Table: see text]
Retrospective study to examine prognostic value of c-reactive protein (CRP) in patients with surgically resected non-small-cell lung cancer (NSCLC).
Authors: Christopher G. Azzoli, Lynn Huynh, Denise Yi, Beilei Cai, Mei Sheng Duh
Journal: Journal of Clinical Oncology (2022)

e20569 Background: This study evaluated the association between baseline elevated CRP and lung cancer outcomes among adults with NSCLC who underwent surgery in the US. Methods: Optum Clinformatics Data Mart in the US (01/2007-09/2020) was used to identify adults with NSCLC who underwent lung cancer surgery and had at least 1 CRP measurement prior to or &gt; 1 month following the index surgery. Baseline CRP levels were defined as the CRP closest to the index surgery in the pre-surgery cohort, and the CRP at least 1-month after in the post-surgery cohort. The association between elevated CRP (&gt; 10 mg/L) and rate of NSCLC recurrence/risk of death was assessed separately for pre-surgery and post-surgery cohorts using multivariate regressions. The overall trend in CRP measurements over a 5-year period was examined using trend tests among those with persistently elevated CRP. Results: For adults in the pre-surgery cohort who had index lung cancer surgery between 2016-2020 (N = 104), after adjusting for age, sex, National Cancer Institute comorbidity, autoimmune disease, peripheral vascular disease, and smoking status, the adjusted-incidence rate ratio (IRR) for NSCLC recurrence was 2.17 (95% confidence interval [CI]: 1.03, 4.60; p &lt; 0.05) among patients with elevated CRP compared with non-elevated CRP. A similar IRR (2.22 [95% CI: 1.05, 4.70]; p &lt; 0.05) was observed among the 264 patients in the post-surgery cohort. Among the 234 patients in the pre-surgery cohort, there was a near two-fold increase in the risk of all-cause death associated with the elevated than the non-elevated CRP groups (odds ratio [OR]: 1.91 [95% CI: 1.06, 3.42]; p &lt; 0.05), and there was a numerically increased risk associated with elevated baseline CRP for the post-surgery cohort (OR: 1.62 [95% CI: 0.88, 2.97]; p = 0.12). Among those with persistently elevated CRP prior to surgery, we observed a significant overall trend of increased CRP levels over the 5-year period. Conclusions: Using real world data in the US, results suggest that an elevated CRP at baseline is associated with a higher risk of NSCLC recurrence and mortality, for both pre- and post-surgery cohorts. An increasing trend of CRP level within 5 years prior to lung cancer surgery indicates the correlation of CRP (as a marker of inflammation) with tumor development. This study adds to a growing body of literature and may shed light into oncology treatments aimed at suppressing tumor-promoting inflammation.
Thyroid gland definitive ultrasound screening in childhood cancer survivors following radiotherapy.
Authors: Julia A. Baran, Stephen Halada, Andrew J. Bauer, Yimei Li, Amber Isaza, Tasleema Patel, Lindsay Sisko, Jill P. Ginsberg, Ken Kazahaya, N. Scott Adzick, Sogol Mostoufi-Moab
Journal: Journal of Clinical Oncology (2022)

10049 Background: Childhood cancer survivors (CCS) are at risk for radiotherapy (RT) late effects, including second malignancies. Optimal screening for thyroid cancer (TC) in CCS post-RT remains controversial. We assessed the clinical benefit of thyroid ultrasound (US) surveillance in CCS exposed to RT. Methods: 316 CCS (175 males) were prospectively surveilled with thyroid US between 2002 and 2021 at the Children’s Hospital of Philadelphia. Patients were screened upon referral to the Survivorship Program. Thyroid US, clinicopathologic features, and endocrine-related outcomes were ascertained. Outcomes were compared using primary CCS diagnosis age cohorts of ≤ 3, &gt; 3 to ≤ 10, and &gt; 10 years. Risk factors for thyroid nodule(s) and TC were evaluated using Kruskal Wallis and ANOVA [OR (95% CI)]. Results: The most common CCS diagnoses were leukemia (32%), CNS tumor (26%), and neuroblastoma (18%). Patients received TBI (43%) and/or RT to craniospinal (43%), chest (13%), and neck regions (7%). About 48% (n = 152) of patients presented thyroid nodule(s) (Table). Forty-six patients underwent surgery, and 28 had TC, including 19 with ATA low-risk, 2 with ATA intermediate-risk, and 7 with ATA high-risk disease. Of the 9 patients with intermediate- or high-risk disease, 5 were ≤ 3 years, 3 were &gt; 3 to ≤ 10 years, and 1 was &gt; 10 years at the time of RT exposure. Eight patients with TC demonstrated pathogenic variant(s). RT exposure at ≤ 3 years old conferred 2-fold increased risk for nodule(s) compared to RT at &gt; 10 years [OR = 2.14 (1.44-2.84) p = 0.03]. Female sex [OR = 1.73 (1.25-2.21) p = 0.02] and greater interval between RT and first US [OR = 1.10 (1.04-1.15) p = 0.001] were additional independent risk factors. Conclusions: Younger age at RT exposure is associated with increased risk of and shorter latency for developing TC. Thyroid US surveillance appears most beneficial in CCS exposed to RT ≤ 3 years old in an effort to diagnose TC at an earlier stage prior to metastasis. [Table: see text]
Immune-related molecular characteristics of Chinese lung cancer patients with different types of <i>ALK</i> rearrangement.
Authors: Xi Li, Yueming Liang, Xiaochun Huang, Xinyi Liu, Mengli Huang
Journal: Journal of Clinical Oncology (2022)

e21144 Background: Anaplastic lymphoma kinase ( ALK) gene rearrangements are found in approximately 5% of non-small-cell lung cancer (NSCLC). Since ALK-TKIs have been developed for patients with ALK-positive advanced NSCLC, it remained 20%-30% non-responders, thus other treatment strategies would be explored to prolong overall survival. Previous studies have shown that ALK rearrangement can upregulate PD-L1 expression via signaling pathways such as ERK/AKT, and the high expression of PD-L1 negatively affects the efficacy of crizotinib and would be more suitable for immunotherapy. However, only a few immunotherapy clinical studies recruited tiny amounts of ALK rearrangement NSCLC, making it difficult to investigate the relationship between this oncogenic gene alteration and therapeutic effects. Herein, we described the immune-related molecular characteristics of ALK-rearranged patients in a large group of Chinese lung cancer, hoping to provide more precise treatment strategies. Methods: A total of 1410 lung cancer patients harboring ALK rearrangement were included in this analysis. Using wide NGS panel testing, we elucidated ALK gene fusions, intergenic region fusions ( ALK-IR) as well as other genomic alterations and TMB levels in each patients’ tumor specimen. PD-L1 expression level was evaluated by the tumor positive score (TPS). Results: Over two hundreds of types of ALK rearrangement were identified. The whole population was divided into six subgroups according to types of ALK rearrangements: 3'- ALK-only (71.1%), 5'-non- EML4-ALK-only (1.0%), multi- ALK fusion (14.2%), single ALK-IR (3.2%), multi-3'- ALK-IR (10.1%), and multi-5'- ALK-IR (0.5%). The overall PD-L1 expression level was high in ALK rearrangement lung cancer, of which the proportion of patients with TPS ≥ 50% was 19.5%, and the TPS ≥ 50% proportion in the single ALK-IR subgroup was the highest (28.6%) among all subgroups. We then evaluated the distribution of TMB levels and found the median TMB level was higher than 30% lung cancer. Of note, the single ALK-IR subgroup also present a trend of higher TMB level among all subgroups. We also observed more DNA damage response (DDR) gene mutations (median number: 2, range: 1-22) in the single ALK-IR subgroup. Somatic copy number amplifications (SCNAs) were detected in 195 (13.8%) ALK -rearranged lung cancer patients, and the proportion of SCNAs in each subgroup was similar. The most frequently high-level amplified genes were MYC (23.9%) and EGFR (10.9%). Furthermore, the 3'- ALK-only subgroup mainly occurred low-level SCNAs (68.5%), whereas the multi- ALK fusion and multi-3'- ALK-IR subgroups were more likely to harbor high and moderate level SCNAs. Conclusions: Our findings demonstrated that lung cancer with ALK-IR might have active immune microenvironment, indicating it’s a subset of ALK-rearranged patients who would benefit from immunotherapy.
Analysis of <i>ROS1</i> fusions in nonlung solid tumors.
Authors: Dong Yan, Mengxiang Xu, Weiran Wang, Yushuai Han, Jianhua Zhu, Tonghui Ma
Journal: Journal of Clinical Oncology (2022)

e15124 Background: Somatic chromosomal fusions involving ROS1 produce chimeric proteins that drive tumorigenesis and progression. Currently, ROS1-directed tyrosine kinase inhibitors (TKIs) are effective treatments for advanced non-small cell lung cancer (NSCLC) patients (pts) with ROS1 fusions. Except for NSCLC, Glioblastoma and spitzoid neoplasms, ROS1 fusions have been rarely reported in other cancers. Therefore, clarifying the patterns and frequency of ROS1 fusions in multi-cancer may help pts benefit from ROS1 inhibit therapy. Methods: To characterize the ROS1-fusion patterns in Chinese pts, we retrospectively analyzed the next-generation sequencing (NGS) data of 11,740 pts from 2017 to 2021. Results: In this study, a total of 12 ROS1 fusions were identified in this Chinese nonlung solid tumors cohort (12/11,740). Among them, the ROS1-fusion positive rate is 0.037% in colonrectal cancer pts (2/5,467), 0.13% in stomach cancer pts (3/2,268), 0.11% in liver cancer pts (2/1,774), 0.19% in kidney cancer pts (1/540), 0.21% in pancreatic cancer pts (2/966) and 0.28% in sarcoma pts (2/725). Particularly, we observed the coexistence of CD80- ROS1 and Intergenic- ROS1 in the same kidney cancer pt. Among ROS1 fusions described in this cohort, the frequency of known partners was 16.67%, and the frequency of unreported partners was 83.33%. Compared with NSCLC (1%̃2%), the ROS1 fusions are less frequent in the nonlung solid tumors (≤0.3%), and fusion partners are mostly unreported, which means that the efficacy of ROS1 TKIs in these solid tumor pts may be different from that in lung cancer. Therefore, more attention and in-depth research are needed in ROS1 fusion positive nonlung solid tumors, which have a low incidence and few cases, so as to bring clinical benefits to more pts. Conclusions: Through NGS, we identified ROS1 fusion patterns in non-lung solid tumors, most of which fusion partners are unreported, expanding the range of ROS1 fusions documented in tumors and providing potential for ROS1 TKIs in multiple tumors.[Table: see text]
MOTION: A randomized, phase 3, placebo-controlled, double-blind study of vimseltinib (DCC-3014) for the treatment of tenosynovial giant cell tumor.
Authors: William D. Tap, Andrew J. Wagner, Maitreyi G. Sharma, Marc Vallee, Mary F. Michenzie, Matthew L. Sherman, Rodrigo Ruiz-Soto, Silvia Stacchiotti, Michiel A.J. van de Sande, Hans Gelderblom
Journal: Journal of Clinical Oncology (2022)

TPS11590 Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths. TGCT is caused by upregulation of the colony-stimulating factor 1 (CSF1) gene, resulting in aberrant CSF1 expression and the recruitment of CSF1 receptor (R)-dependent inflammatory cells. Resection is the primary treatment, but nonsurgical treatment options are necessary for patients with symptomatic TGCT not amenable to surgical resection. Vimseltinib is an oral switch control TKI specifically designed to selectively and potently inhibit CSF1R. In a Phase 1/2 study in patients with TGCT, vimseltinib showed encouraging antitumor activity with an overall objective response rate (ORR) of 42% in the cohort receiving 30 mg twice weekly (recommended phase 2 dose; Gelderblom et al, ESMO 2021 Poster). Vimseltinib was also well tolerated, and the majority of the common (≥15%) treatment-emergent adverse events (TEAEs) were Grades 1–2. Among these common TEAEs, the only Grade 3–4 event in the Phase 2, twice-weekly, 30-mg cohort was increased blood creatine phosphokinase (CPK); however, this elevated CPK was not associated with any symptoms (Gelderblom et al, ESMO 2021 Poster). Phase 1/2 efficacy and safety data support further development of vimseltinib; here, we describe the ongoing Phase 3 study for patients with TGCT not amenable to surgical resection. Methods: MOTION (NCT05059262) is a Phase 3, randomized, placebo-controlled, double-blind study that aims to evaluate the efficacy and safety of vimseltinib for the treatment of TGCT not amenable to surgical resection. Participants must be at least 18 years of age and have histologically confirmed and symptomatic TGCT for which surgical resection will potentially cause worsening functional limitation or severe morbidity. Prior CSF1R therapy is not permitted (previous imatinib and nilotinib is allowed). In Part 1 of the study, eligible participants will be randomized 2:1 to receive either vimseltinib 30 mg twice a week or matched placebo for 24 weeks. The primary outcome measure is ORR assessed by central read using Response Evaluation Criteria in Solid Tumors version 1.1 at 25 weeks. Secondary outcome measures include ORR per tumor volume score, range of motion, and patient-reported outcomes. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib in Part 2, a long-term treatment phase in which participants will receive open-label vimseltinib. This international study plans to randomize 120 participants and is currently enrolling. Clinical trial information: NCT05059262.
CCTG PR21: A randomized phase II study of [<sup>177</sup>lu]lu-PSMA-617 verus docetaxel in patients with metastatic castration-resistant prostate cancer and PSMA-positive disease (NCT04663997).
Authors: Kim N. Chi, Fred Saad, Wendy R. Parulekar, Urban Emmenegger, Sebastien J. Hotte, Frederic Pouliot, Glenn Bauman, Katherine A. Zukotynski, Stuart Peacock, Alexander William Wyatt, Jean-Mathieu Beauregard, Justin Lee, Carlos Uribe, Conor Dellar, Keyue Ding, Francois Benard
Journal: Journal of Clinical Oncology (2022)

TPS5110 Background: [ 177 Lu]Lu-PSMA-617 improves outcome in men with metastatic, PSMA positive CRPC post androgen pathway inhibitor therapy and taxane chemotherapy compared to standard care (excluding chemotherapy, immunotherapy, radium-223 and investigational drugs; Sartor et al, NEJM 2021). The relative efficacy, adverse event experience and impact on QOL of [ 177 Lu]Lu-PSMA-617 compared to docetaxel chemotherapy in this patient population is unknown. We hypothesize that [ 177 Lu]Lu-PSMA-617 will improve radiographic PFS (rPFS) compared to docetaxel chemotherapy with a favourable safety and tolerability profile. Methods: CCTG PR21 is a Canadian Cancer Trials Group randomized phase II trial with a primary objective to compare rPFS between [ 177 Lu]Lu-PSMA-617 7.4 GBq (+/- 10%) IV q 6 weekly (maximum 6 cycles) versus docetaxel 75 mg/m 2 q 3 weekly (maximum 12 cycles). Secondary objectives are to compare the two arms with respect to: 6-month PFS rate (PCWG3 and RECIST 1.1), second rPFS after crossover to the alternate therapy, time to commencement of 3 rd line systemic therapy, OS, PSA decline from baseline, clinical benefit rate and adverse events. Tertiary objectives include evaluation of QOL (FACT-P and EQ5D-5L), cost effectiveness, ctDNA and radiographic based prognostic and predictive biomarkers, dosimetry based approach to measurement of [ 177 Lu]Lu-PSMA-617 activity and creation of tissue and image biobanks. Key eligibility criteria include: mCRPC with PSMA positive disease using 18 F or 68 Ga radionuclide label, progression on ADT + ARPI therapy (using PSA, RECIST 1.1 or PCWG3 criteria) and adequate organ function. Statistical Design: Patients are allocated in 1:1 ratio to [ 177 Lu]Lu-PSMA-617 or docetaxel balanced for stratification factors of ECOG PS, LDH, visceral metastases, previous docetaxel in the castration sensitive setting &gt; 1 year prior to enrollment as well as centre. Assuming a 6-month median rPFS for the control group, the detection of a hazard ratio (HR) of 0.67 with 80% power using a 1-sided 5% level test will require accrual of 200 participants in 24 months with 12-month follow-up to trigger the primary analysis. Conduct to Date: Study activation Dec 17 2020. Enrollment as of January 31 2022: 25. The DSMC last reviewed and recommended continuation of the trial in December 2021. Clinical trial information: NCT04663997.